Developmental dyslexia is a disorder manifested by difficulty in learning to read and write despite conventional instruction, adequate intelligence and sociocultural opportunity. As has been observed in numerous psychophysical investigations and dozens of functional brain imaging studies, the disease is dependent upon fundamental cognitive disabilities of a constitutional origin. Dyslexia affects mainly school-age children with prevalence as high as 8%, yet the symptom usually perpetuates into adulthood, leaving psychological and economical distress for the individual and the society. Epidemiology studies have established inheritance as a major etiology. The segregation analysis suggests that there may be major gene(s) responsible for the trait which renders the disorder accessible to a wide range of molecular genetic approaches, most notably, linkage based positional cloning. The characterization of the gene(s) responsible for dyslexia will not only provide a basis for better therapeutic intervention of the disease, but also profoundly enrich our knowledge on some of the fundamentals of neurobiology and cognitive sciences, i.e., the molecular mechanisms governing the development and maturation of the cortical structures which are involved in human language, learning, memory and hemispheric lateralization. We are collaborating with clinical investigators at Harvard and Yale Universities and the Karolinska Institute at Sweden to gather dyslexia pedigrees and affected relative pairs for a genetic linkage study aimed at localizing the major gene(s) for the trait. Such samples promise a highly accurate diagnosis and will have sufficient statistical power to determine or reject linkage of a major gene under a polygenic background. We are also developing a new approach to studying polygenic traits should linkage study fail to identify the major gene(s).